Download Use of hormone replacement therapy before and after ovarian

Int. J. Cancer: 119, 2907–2915 (2006)
' 2006 Wiley-Liss, Inc.
Use of hormone replacement therapy before and after ovarian cancer
diagnosis and ovarian cancer survival
Chantal Mascarenhas1,2, Mats Lambe1, Rino Bellocco1,3, Kjell Bergfeldt4, Tomas Riman5,6, Ingemar Persson1,7
and Elisabete Weiderpass1,8*
1
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
2
Centre for Molecular Epidemiology, Yong Loo Lin School of Medicine. The National University of Singapore, Singapore
3
Department of Statistics, University of Milan-Bicocca, Milan, Italy
4
Department of Gynecologic Oncology, Karolinska University Hospital, Stockholm, Sweden
5
Department of Obstetrics and Gynecology, Falu Hospital, Falun, Sweden
6
Center for Clinical Research, Dalarna, Sweden
7
Medical Products Agency, Uppsala, Sweden
8
Cancer Registry of Norway, Montebello, Oslo, Norway
Use of hormone replacement therapy (HRT) has been hypothesized to affect survival of epithelial ovarian cancer (EOC). We
studied 5-year survival in patients with invasive EOC and borderline ovarian tumors (BOT) according to HRT use before and after
diagnosis in a prospective nation-wide cohort study of 799 women
diagnosed with EOC (n 5 649) and BOT (n 5 150) aged 50–74
years in 1993–1995 in Sweden. Cox regression was used to obtain
multivariate age-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Multivariate models included indicator variables for age, tumor stage, grade and histological subtype. After 5
years of follow-up, 45% of the patients with EOC and 93% of the
patients with BOT were alive. For women with BOT there were
no associations between HRT-use pre- or postdiagnosis and survival. There was no overall difference in 5-year EOC survival
according to use HRT before diagnosis (multivariate HR 5 0.83,
95% CI 5 0.65–1.08), except for serous EOC (HR 5 0.69, 95% CI
5 0.48–0.98). Analyses of different HRT preparations, duration
and recency of use did not reveal any variations in pattern of survival. We observed a better survival for EOC-patients who used
HRT after diagnosis (multivariate HR 5 0.57, 95% CI 5 0.42–
0.78). We conclude that HRT-use prior to diagnosis of EOC does
not affect 5-year survival, except for a possible survival advantage
in serous EOC. Women using HRT after diagnosis had a better
survival than women with no use, but we cannot rule out that this
latter finding may reflect a subtle selection process.
' 2006 Wiley-Liss, Inc.
Key words: ovarian cancer; hormonal replacement therapy; survival;
mortality; Sweden
Hormonal factors are believed to be of fundamental importance
in the etiology of ovarian cancer, the 6th most frequent type of
female cancer in the world.1 Ovarian cancer is usually associated
with a rather poor prognosis, with overall 5-year survival rates
commonly less than 40%.2
In recent decades in Sweden, HRT has been widely used for
relief of climacteric symptoms and to prevent osteoporosis. Progestins without estrogens are mainly used for the treatment of climacteric bleeding irregularities, and for the alleviation of symptoms related to benign appearing ovarian cysts. Estriol can be
bought over the counter, and is mostly used for symptomatic treatment of vaginal or urethral atrophy among elderly women.3,4
While effectively relieving women of climacteric symptoms,
use of menopausal hormones has been shown to increase risks of
different types of cancer. For breast cancer, there is growing evidence that cyclically combined estrogen–progestin therapy increase risk even more than estrogens alone.5–8 For endometrial
cancer estrogens alone increase risk substantially, as do use of
cyclically combined estrogen–progestins.8–10 For epithelial ovarian cancer (EOC) estrogen without progestins, or cyclically combined estrogen–progestins therapy increases risk.8,11,12 There are
few studies on the effects of regimens of estrogens continuously
Publication of the International Union Against Cancer
combined to progestins: this type of regimen seems to increase
risk of breast cancer,5,13 has not affect11 or increase risk14 of EOC
and to decrease9 or have no effect14 on risk of endometrial cancer.
Most importantly, use of HRT may increase risk of coronary heart
disease, venous thrombosis and stroke.7,15–17
To date only a few studies18–23 have investigated the possible
association between use of hormone replacement therapy (HRT)
and ovarian cancer mortality or survival. On the basis of limited
sample sizes, the results of these studies have been inconsistent. In
the only large prospective study19,22 postmenopausal estrogen use
for 10 or more years before cohort enrolment (and cancer diagnosis) was associated with and increased risk of ovarian cancer mortality that persisted up to 29 years after cessation of use. All studies investigating HRT use following diagnosis of ovarian cancer
found it to be unrelated to survival.18,20,21,23
Our aim in the present study was to examine whether use of
HRT before or after diagnosis of ovarian cancer affects 5-year
survival. To our knowledge, this is the first study to investigate in
detail ovarian cancer survival patterns according to HRT use both
before and after diagnosis. Since use of HRT most likely affects
the risk of developing ovarian cancer,12 it is plausible that use
would also influence survival, although the underlying biological
mechanisms remain unclear.
Our study was based on a follow-up of patients who previously
participated in a nation wide population-based case–control study
in Sweden. Our study demonstrated an increased risk of EOC
among ever-users compared with never users of HRT containing
estrogens opposed by sequential progestins (OR 5 1.53; 95%
CI 5 1.15–2.05), and the highest risks were observed among those
who had used this type of HRT for more than 10 years. Ever-use
of estrogens continuously combined with progestins was unrelated
to EOC risk (OR 5 1.02; 95% CI 5 0.73–1.43). Estriol, a hormone sold over the counter in Sweden and considered by many as
a ‘‘weak’’ estrogen, was not associated with ovarian cancer risk.11
Subjects and methods
Founding case–control study
In short, women were 50–74 years of age at study enrolment,
born in and residents of Sweden, and had at least one intact ovary
Grant sponsors: The Swedish Cancer Society and Gustav V Jubilee
Foundation, Sweden.
*Correspondence to: Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden. Fax: 146-8-314975.
E-mail: [email protected]
Received 23 November 2005; Accepted after revision 9 June 2006
DOI 10.1002/ijc.22218
Published online 22 September 2006 in Wiley InterScience (www.interscience.
wiley.com).
2908
MASCARENHAS ET AL.
(women with bilateral oophorectomy were excluded). The recruitment period extended from October 1, 1993, to December 31,
1995. Eligible case patients were previously free of ovarian malignancies and presented with a newly diagnosed, histologically confirmed, invasive or borderline epithelial ovarian tumor. Patients
were identified through reports to 6 regional cancer registries that
together provide a complete nationwide cancer registration.24
After being informed about the study by their physicians, case
patients agreeing to participate signed an informed consent form
before study enrolment. A total of 1,205 women with incident
ovarian tumors of any histological type were reported to the regional cancer registries, and 914 patients (76%) initially agreed to
participate. Of these, 8 women declined participation in the present follow-up survival study, and 1 was excluded due to the physicians’ denial of access to patient records. Of the 905 remaining
cases, 68 had non-EOC; 13 other gynecologic malignant tumors; 1
record revealed relapse of a previous ovarian cancer diagnosed in
1991; 5 were intestinal cancers; 2 were benign tumors and 17 were
described as cancers of the abdomen and peritoneum, according to
pathological reevaluation during the patient’s treatment in the
clinics. The final study population consisted of 799 women with
ovarian cancer, of which 150 had borderline epithelial ovarian
tumors (BOT) and 649 invasive EOC. The histological classification was based on pathology reports alone.
Exposure data were collected through mailed self-administered
questionnaires that covered demographic, medical, gynecological,
reproductive and lifestyle factors including questions on height,
weight, diet, physical activity, heredity, previous disease, gynecological surgery, pregnancies, births, menstruations and number of
visits to gynecologists (prior to diagnosis). In 50% of the cases,
the requested information was supplemented with a telephone
interview to further enhance the accuracy of information attained.
Detailed information pertaining to HRT and oral contraceptives
was obtained. To facilitate the recall of oral contraceptives and
HRT use, the questionnaire showed pictures of all the HRT brands
commercially available in Sweden beginning in the 1950s.
Present cohort study and follow-up
All information on HRT use before cancer diagnosis was obtained through the initial questionnaire pertaining to exposure
data, answered at enrolment in the founding case–control study.11
The HRT exposure variables were classified as estrogen only
(ERT––medium potency estrogens, i.e. conjugates estrogens, estradiol and other synthetic estrogens without added progestins);
estrogens with progestins combined cyclically (<16 days/cycle,
most commonly 10 days/cycle) or continuously (19 days/cycle,
most commonly 28 days/cycle). Information was also obtained on
low potency estrogens (oral or vaginal estriol, dienestriol or low
dose estradiol [25 lg/day]). In addition, information was available
on progestin only therapy used in the treatment of perimenopausal
bleeding irregularities and for the alleviation of symptoms related
to benign appearing ovarian cysts. For HRT treatment, women
were categorized as never users, exclusive users of only one HRT
regimen and nonexclusive users who over time had taken more
than one type of HRT. We calculated duration and recency of
HRT use separately for each type of regimen (i.e. estrogens only,
estrogens combined with progestins cyclically, estrogens combined with progestins in a continuous way and overall estrogens
combined with progestins) and overall duration and recency of use
for any type(s) of HRT taken. We categorized duration of use as
never users; less than or equal to 3 years of use and greater than 3
years. All exposures were censored after an index date, which was
defined as 3.0 months before the date of diagnosis for each patient.
Women who used any type of HRT at the index date were defined
as current users. Former users were all other users that were not
current users.
Finally, we looked at the combined effects of duration and
recency of any HRT treatment received by patients. This combined variable was classified as never users at baseline; current
users and former users of shorter or longer duration (3, >3
years). We could only consider these combined overall effects for
women who had complete information for both, duration and
recency of HRT use. Missing information was encountered when
some women recalled HRT use, but not the specific duration or
recency of use.
Other relevant data obtained from the initial questionnaires
included socioeconomic status, duration of use of oral contraceptives, body mass index (BMI––defined as weight in kilograms divided by height in meters squared), smoking status 1 year prior to
diagnosis, parity, age at menarche and menopause, history of tubal
ligation and a family history of ovarian cancer in the mother or
sister of the patient.
Additional patient data required for the present follow-up survival study included information on use and duration of HRT after
diagnosis, and detailed clinical information on tumor characteristics, treatment modalities, recurrence and progression of the disease. Such data was abstracted from medical records by visits to 7
regional departments of gynecologic oncology, where all cases of
ovarian cancer, with very few exceptions, are referred for treatment. For completion of the records, the referring local departments of gynecology and obstetrics in all 52 departments in hospitals throughout Sweden were visited in years 2000 and 2001. For
this purpose, 2 oncology nurses were specifically trained for data
abstraction. The information in the medical records was compiled
into a comprehensive abstracting form with a manual for standardization of the data retrieval. Furthermore, an administrative database was constructed to facilitate the tracking of data sources and
flow of information from the various hospitals.
Exposure information pertaining to HRT use after diagnosis
was recorded on ever/never use, start and stop dates of treatment
and if HRT treatment was ongoing at the time of data abstraction.
If nothing was specifically stated in the patients’ medical records
about prescriptions of any type of HRT, it was recorded in the
abstracting form as ‘‘not stated.’’ After consultation with local
gynecological oncologists, we reclassified ‘‘not stated’’ as ‘‘not
users,’’ since HRT are only sold or used under medical prescription in Sweden (except for low potency estrogens), and the absence of a prescription in the medical record of a cancer patient
means with great certainty that HRT was not used. Information
was not available for all patients about specific types of HRT prescribed after diagnosis, or if patients changed types of HRT. We
categorized duration of use of HRT after diagnosis as never users;
less than 1 year; 1–2 years and greater than 2 years. Information
on prognostic factors included FIGO (International Federation of
Gynecology and Obstetrics) stage (I, II, III, IV), WHO grade of
differentiation (well differentiated, moderately differentiated and
poorly differentiated), tumor size at diagnosis, residual tumor size,
the presence of multiple simultaneous primary tumors, histological subtype (serous, mucinous, endometrioid, clear cell, undifferentiated, others), reasons for primary diagnosis (gynecological
routine examination, the presence of symptoms, and other reasons)
and treatment.
Abstraction of medical record data was successful for 770
women in the cohort (96% of all cases in the original study) that
included the retrieval of 1,095 medical records (since each patient
could have more than one medical record) in different clinics or
hospitals. Information was successfully retrieved in 99.9% of
these cases concerning FIGO stage, 75% for tumor grade, 100%
for treatment and in 99% concerning follow-up of the events indicating recurrence in the 5-year follow up period. A gynecological
oncologist double-checked the abstracted information for inconsistencies, incompleteness or doubtful information, which was
then verified against the original records or with the treating physicians.
We considered as outcomes overall mortality (death from any
cause) and cause specific mortality (death from ovarian cancer or
related causes). We did not evaluate ovarian cancer recurrence in
the present report.
HRT AND OVARIAN CANCER SURVIVAL
Date and cause of death information was obtained through record linkage with a nationwide Cause of Death Register updated
through December 31, 2002, using the individually unique
national registration number. For consistency it was decided to
use information on cause of death from the register and not the
abstracted medical records data. The agreement between these 2
sources was 99.1%. Causes of death were classified according to
The International Statistical Classification of Diseases and Related
Health Problems (ICD) versions 9 and 10.
Causes of ovarian cancer deaths were defined as women dying
from ovarian cancer (ICD-9 codes 183.0-183.9) and C56 (ICD-10)
or having ‘‘malignant tumor in the ovary’’ as the underlying cause
of death. Related causes of death were considered as death from
possibly metastatic tumors, such as unspecified location of malignant tumor in the peritoneum (n 5 1), several malignant tumors
with different points of origin (n 5 1), tumor of uncertain nature
in the ovary (n 5 1) and malignant tumor in the uterus except isthmus uteri (n 5 2).
The Ethics Committees of the Karolinska Institutet, Sweden,
approved the study.
Statistical methods
Overall survival time was defined as the time interval from the
date of ovarian cancer diagnosis to the date of death from any
cause. Cause-specific survival was defined as the time interval
from the date of diagnosis to the date of death from ovarian cancer
or related causes. All patients were followed for 5 years or until
death. The end of follow-up for the analyses presented here was
set to December 31, 2002.
STATA1 Version 8.2 was used for data analyzes. Contingency
tables and univariate summary measures were produced to
describe the patients at the beginning of follow-up, in term of the
hormone exposure variables and prognostic factors. Kaplan–Meier
estimates and graphs were produced to describe the overall and
stratified survival distribution. The log rank test was used to assess
whether there was any statistical difference and those variables
with a p-value less than 0.25 were considered eligible to be
included in the multivariate analysis.25
In an initial step prior to multivariate analyses, graphical assessments were performed for all covariates to assess the proportionality assumptions.
The Cox proportional hazard regression model was subsequently fit to estimate the effect of HRT and its derived variables,
adjusted by variables found to be important in the first part of the
analysis: age, FIGO stage, WHO grade of differentiation and histological subtype of tumor. We used the likelihood ratio test based
on the partial likelihood to assess the independent effect of the explicative variables as well as the interaction terms. Appropriated
goodness-of-fits and diagnostic measures, together with graphic
methods, based on the Schoenfeld and Martingales residuals26
were ultimately produced to assess the appropriateness of the
models chosen, such as the proportionality assumption underlying
the Cox model.
Tests of association used in the analyses to test significance
between groups were the likelihood ratio test and Pearson’s v2
tests.
Results
Among the 799 patients studied, 347 died from ovarian cancer
or related causes and 22 died for other reasons after 5 years of follow-up. There were 649 cases of EOC and 150 cases with BOT,
and they were analyzed separately.
Invasive EOC
After 5 years of follow-up, 290 (45%) of the 649 women with
EOC were alive, and 359 dead: 344 deaths were due to ovarian
cancer and 22 were due to other causes. In the following only
2909
results from the cause-specific analyses will be reported in detail,
as they did not differ substantially from the overall mortality.
As expected, elderly women had a poorer survival, while use of
oral contraceptives, BMI before diagnosis, smoking, age at menarche and menopause, parity, family history of ovarian cancer and
tubal ligation were unrelated with survival, as shown in Table I.
A significantly better survival was evident in women who were
diagnosed through their routine gynecological examination
(hazard ratio, HR 5 0.47, 95% CI 5 0.29–0.76), compared to
women that were diagnosed primarily through the presentation of
symptoms. The highest probability of death was observed in
women with a FIGO stage IV tumor (HR 5 13.82, 95% CI 5
8.99–21.26) relative to those presenting with a FIGO stage I tumor. Compared to women with well-differentiated tumors
(according to the WHO grade of differentiation classification),
women with moderately and poorly differentiated tumors had a
worst survival (HR 5 2.46, 95% CI 5 1.49–4.06; and HR 5 3.94,
95% CI 5 2.46–6.31, respectively). For residual tumor size after
primary surgery, women with tumors greater than 2 cm had 1.43
(95% CI 5 0.99–2.08) times the probability of dying from ovarian
cancer compared to women with a residual tumor size less than
2 cm. However, the greatest probability of death was observed in
women whose tumors were nonmeasurable due to difficulties in
quantifying the residual tumor mass at time of surgery (HR 5
2.32, 95% CI 5 1.57–3.44). The majority of the ovarian tumors
was of serous subtype (n 5 326), followed by endometrioid (n 5
168), mucinous (n 5 62) and other types (n 5 79). Women with
mucinous type of ovarian tumor had a slightly better survival than
women with other histological types of EOC (Table I).
Use of HRT before EOC diagnosis
In total, HRT was used by 166 women (26%) before EOC diagnosis. Overall, there were no clear differences in EOC survival
between women that had used any type of HRT compared to never
users (multivariate adjusted HR 5 0.83; 95% CI 5 0.65–1.08)
(Table II).
Use of different types of HRT before diagnosis (exclusive users
of estrogen, estrogens with cyclically added progestins, estrogens
with continuously added progestins and combined estrogens and
progestins) was not associated with EOC survival. Duration or
recency of use of HRT before diagnosis––considered separately or
in combination––were not associated with survival (Table II). The
majority of women (68%) who had ever used HRT had done so in
the year preceding ovarian cancer diagnosis.
There was no clear difference in risk of death between exclusive
and nonexclusive users of any type of HRT. However, the patterns
observed for estrogen only (nonexclusive use), estrogen with continuously added progestins (both for exclusive and nonexclusive
use) and combined estrogen–progestin (nonexclusive use) are suggestive of better survival in users, albeit nonsignificant (Table II).
Use of estriol (administrated orally or vaginally) before diagnosis was rare, and not associated with EOC survival (Table II). In
the following we will present results on HRT use overall and
according to different combinations disregarding use of estriol.
The proportion of HRT users and nonusers before diagnosis
was similar among women being diagnosed with different tumor
FIGO stages (Stage I 5 29% users, 28% nonusers; Stage II 5
13% users,11% nonusers; Stage III 5 46% users, 46% nonusers;
Stage IV 5 12% users, 14% nonusers) WHO grade of differentiation (well differentiated 5 13% users, 14% nonusers; moderately
differentiated 5 26% users, 26% nonusers; poorly differentiated 5
54% users, 51% nonusers, not stated 5 8% users, 9% nonusers)
and histological ovarian tumor subtypes (Table II). Diagnosis
through routine gynecological examination was more frequent
among users of HRT compared to never users (13.9–7.1%, respectively), notably for diagnosis of highly differentiated FIGO stage I
tumors.
2910
MASCARENHAS ET AL.
TABLE I – INVASIVE EOC SURVIVAL 5 YEARS AFTER DIAGNOSIS ACCORDING TO DIFFERENT CHARACTERISTICS OF THE STUDY POPULATION
(ONLY DEATHS DUE TO OVARIAN CANCER ARE PRESENTED)
No. cases
(total 649)
Ovarian cancer deaths
(total 344) [n (%)]
Age at diagnosis (years)
50–54
141
55–59
134
60–64
118
65–69
125
70–75
131
Reasons for diagnosis
°Routine examination
58
°Symptoms
572
°Other reasons
15
°Not stated
4
FIGO stage
I
185
II
74
III
301
IV
89
WHO grade of differentiation
Well differentiated
89
Moderately differentiated
170
Poorly differentiated
333
Not stated
57
1
Residual tumor size at 1st surgery
<2 cm
86
>2 cm
76
Nonmeasurable
53
Not stated
173
Histological subtype
Serous
326
Mucinous
62
Endometrioid
168
Others
79
Unclassified histology
14
Any HRT use before diagnosis2
Never
467
Ever
166
No information
16
1
HRT use after diagnosis
Never
499
Ever
150
Use of oral contraceptives3
Never
433
Ever
174
3
BMI before diagnosis
<20
8
20–24.99
298
25–29.99
223
301
81
Smoking3
Never
400
Current
111
Former
120
Age at Menarche
13 years
341
>13 years
308
Age at Menopause
50
394
>50
255
Parity3
0
121
1–2
356
3–4
142
51
16
Family history ovarian cancer (mother or sister)
No
554
Yes
37
Do not know
40
Tubal ligation3
No
620
Yes
15
Median survival
(years)
Age adjusted 5 year survival
(% alive after 5 years)
HR or risk or death 5 years after
EOC diagnosis (95% CI) age adjusted
70 (50)
57 (42)
64 (54)
76 (61)
77 (59)
>5
>5
4.25
3.21
3.35
50
57
45
38
40
1.00 (reference)
0.77 (0.55–1.10)
1.11 (0.79–1.55)
1.35 (0.97–1.86)
1.31 (0.95–1.81)
18 (31)
317 (55)
7 (47)
2 (50)
>5
3.96
4.61
1.90
68
44
47
50
0.47 (0.29–0.76)
1.00 (reference)
0.83 (0.39–1.76)
1.00 (0.25–4.01)
29 (16)
27 (36)
207 (69)
81 (91)
>5
>5
2.83
1.96
84
63
30
9
1.00 (reference)
2.60 (1.54–4.40)
6.87 (4.64–10.17)
13.82 (8.99–21.26)
19 (21)
78 (46)
216 (65)
31 (54)
>5
>5
3.17
3.92
78
54
34
45
1.00 (reference)
2.46 (1.49–4.06)
3.94 (2.46–6.31)
3.27 (1.84–5.80)
54 (63)
56 (74)
47 (89)
127 (73)
3.62
2.44
1.68
2.53
37
25
11
26
1.00 (reference)
1.43 (0.99–2.08)
2.32 (1.57–3.44)
1.40 (1.02–1.94)
184 (56)
22 (35)
80 (48)
49 (62)
9 (64)
4.03
>5
>5
3.24
2.76
42
63
52
38
36
1.00 (reference)
0.57 (0.37–0.89)
0.78 (0.60–1.01)
1.20 (0.88–1.64)
–
251 (54)
82 (49)
11 (69)
4.03
>5
2.76
46
50
31
1.00 (reference)
0.92 (0.71–1.18)
–
293 (59)
51 (34)
3.44
>5
41
66
1.00 (reference)
0.46 (0.34–0.63)
240
83
3.97
>5
45
51
1.00 (reference)
0.89 (0.67–1.17)
5
157
119
41
2.46
4.43
4.12
4.92
39
46
46
50
1.34 (0.55–3.27)
1.00 (reference)
1.00 (0.79–1.27)
0.93 (0.66–1.30)
224
51
58
3.88
>5
>5
44
50
50
1.00 (reference)
0.81 (0.60–1.11)
0.84 (0.63–1.12)
184
160
4.37
4.25
46
47
1.00 (reference)
0.97 (0.78–1.20)
212
132
4.51
4.12
46
46
1.00 (reference)
0.97 (0.78–1.20)
69
174
83
9
3.51
>5
3.68
4.47
42
51
41
34
1.00 (reference)
0.78 (0.59–1.03)
1.02 (0.74–1.41)
0.73 (0.36–1.45)
284
26
22
4.61
3.58
4.43
48
29
41
1.00 (reference)
1.39 (0.93–2.12)
1.00 (0.64–1.54)
328
7
4.37
>5
46
47
1.00 (reference)
0.88 (0.42–1.87)
1
Information available for 388 patients (284 deaths, or 73%) who underwent surgery.–2HRT, hormone replacement therapy (medium potency
estrogens with or without progestins) before diagnosis of cancer, regardless of estriol use.–3Missing information for oral contraceptives 42
patients (21 deaths), for BMI before diagnosis: 39 patients (22 deaths), smoking 18 patients (11 deaths), parity 14 patients (9 deaths); tubal ligation: 14 patients (9 deaths).
2911
HRT AND OVARIAN CANCER SURVIVAL
TABLE II – USE OF HORMONE REPLACEMENT THERAPY (HRT) BEFORE THE DIAGNOSIS OF INVASIVE EPITHELIAL OVARIAN CANCER AND SURVIVAL
Total no.
of cases
(n 5 633)
Deaths
[n (%)] total
333 (53%)
Age adjusted
median survival
(years)
Any HRT1 use
Never
467
251 (54)
Ever
166
82 (49)
Duration of use 3 years
86
44 (51)
Duration of use >3 years
72
35 (49)
Current users
108
49 (45)
Former users
52
31 (60)
Estrogen only treatment (ERT)1,4
Exclusive users
33
18 (55)
Nonexclusive users
27
10 (38)
6
Duration of use 3 years
27
13 (48)
Duration of use >3 years6
28
13 (46)
6
Current users
25
11 (44)
Former users6
30
15 (50)
Estrogens and cyclically added progestins1
Exclusive users
54
28 (52)
Nonexclusive users
29
11 (37)
6
Duration of use 3 years
49
21 (43)
Duration of use >3 years6
28
15 (54)
6
Current users
50
23 (46)
6
Former users
27
13 (48)
1
Estrogens and continuous combined progestins
Exclusive users
26
10 (38)
Nonexclusive users
27
11 (41)
6
Duration of use 3 years
33
13 (39)
Duration of use >3 years6
16
5 (31)
6
Current users
34
14 (41)
6
Former users
15
4 (27)
Combined estrogens and progestins (cyclically or continuously)1
Exclusive users
80
38 (48)
Nonexclusive users
39
16 (41)
Duration of use 3 years6
68
29 (43)
Duration of use >3 years6
43
20 (46)
6
Current users
81
37 (46)
6
Former users
30
12 (40)
Estriol
Vaginally
Never
546
290 (53)
Ever
86
43 (50)
Orally
Never
560
294 (53)
Ever
72
39 (54)
1
Serous tumors
Never used HRT
239
142 (59)
Ever used HRT
87
42 (48)
Current users (all)
58
29 (50)
Former users
26
12 (46)
Mucinous tumors1
Never used HRT
46
16 (35)
Ever used HRT
16
6 (38)
Current users
10
1 (10)
Former users
4
4 (100)
1
Endometrioid tumors
Never used HRT
124
58 (47)
Ever used HRT
42
20 (48)
Current users
28
12 (43)
Former users
13
8 (61)
Other tumors1
Never used HRT
58
35 (60)
Ever used HRT
21
14 (67)
Current users
12
7 (58)
Former users
9
7 (62)
Age adjusted
5 year
survival (%)
Hazard ratio
(95% CI)
age adjusted
Hazard ratio (95% CI)
(adjusted age, FIGO stage
and WHO grade)
4.29
4.79
4.03
>5
>5
4.12
46
49
42
51
53
43
1.00 (reference)
0.92 (0.71–1.18)
1.00 (0.72–1.39)
0.87 (0.61–1.24)
0.87 (0.63–1.20)
1.05 (0.72–1.52)
1.00 (reference)
0.83 (0.65–1.08)2,3
0.87 (0.62–1.21)
0.79 (0.56–1.13)
0.75 (0.54–1.03)
1.01 (0.69–1.47)
3.89
>5
>5
>5
4.25
>5
48
64
52
56
48
78
0.93 (0.58–1.51)
0.57 (0.30–1.08)
0.84 (0.48–1.47)
0.72 (0.41–1.27)
0.78 (0.42–1.46)
0.70 (0.41–1.20)
–5
>5
>5
>5
4.44
>5
>5
52
61
57
48
56
52
1.12 (0.74–1.69)
0.64 (0.35–1.17)
0.83 (0.52–1.31)
1.10 (0.65–1.86)
0.95 (0.61–1.48)
0.89 (0.51–1.56)
–5
>5
>5
>5
>5
>5
>5
57
59
58
70
57
75
0.68 (0.36–1.29)
0.65 (0.36–1.20)
0.72 (0.41–1.26)
0.48 (0.20–1.16)
0.74 (0.43–1.27)
0.41 (0.15–1.11)
–5
>5
>5
>5
>5
>5
>5
53
59
52
58
54
59
0.95 (0.67–1.36)
0.67 (0.40–1.11)
0.80 (0.54–1.19)
0.88 (0.56–1.39)
0.90 (0.63–1.29)
0.68 (0.38–1.03)
–5
4.36
4.92
46
50
1.00 (reference)
0.86 (0.62–1.18)
–5
4.49
4.03
47
44
1.0 (reference)
0.91 (0.65–1.29)
–5
3.56
5.0
3.80
>5
40
50
42
53
1.00 (reference)
0.74 (0.52–1.06)
0.83 (0.54–1.26)
0.65 (0.36–1.17)
1.00 (reference)
0.69 (0.48–0.98)7
0.72 (0.47–1.09)
0.61 (0.34–1.11)
>5
>5
>5
–8
64
61
98
–8
1.00 (reference)
1.13 (0.43–2.97)
0.19 (0.02–1.51)
6.43 (1.72–23.99)
1.00 (reference)
1.94 (0.52–7.21)2
0.60 (0.06–5.92)
3.06 (0.39–23.70)
>5
>5
>5
3.3
53
52
56
33
1.00 (reference)
1.05 (0.63–1.74)
1.00 (0.54–1.87)
1.24 (0.59–2.62)
1.00 (reference)
1.10 (0.65–1.85)2
0.92 (0.49–1.75)
2.05 (0.94–4.46)
4.26
4.79
>5
4.20
40
33
42
38
1.00 (reference)
1.26 (0.66–2.39)
1.27 (0.52–3.12)
1.24 (0.55–2.80)
1.00 (reference)
1.04 (0.54–2.02)2
1.03 (0.39–2.72)
1.05 (0.45–2.42)
1
HRT, hormone replacement therapy (medium potency estrogens with or without progestins), disregarding use of estriol.–2Inclusion of the
variable ‘‘HRT after diagnosis’’ in this analysis did not change the risk estimates meaningfully).–3Addition in the model of an indicator variable
for histological type entail an HR of 0.84 (95% CI 5 0.65–1.08).–4ERT, estrogen replacement therapy.–5Adjustment for FIGO stage, and WHO
grade was not possible due to small numbers.–6Exclusive and nonexclusive users combined.–7Inclusion of HRT after diagnosis in this model
entail an HR 5 0.74 (95% CI 5 0.52–1.08).–8Lack of data due to few observations.
In Table II we also show the multivariate modeling for hazard
estimates including indicator variables for stage and grade of tumor differentiation according to different aspects of HRT use.
Except for an indication of better 5-year survival among users of
HRT diagnosed with serous tumor (HR 5 0.69, 95% CI 5 0.48–
0.98 after controlling for FIGO stage and WHO degree of differentiation at diagnosis) no evidence of better survival was observed. When we added an indicator variable for HRT use after
2912
MASCARENHAS ET AL.
TABLE III – MULTIVARIATE SURVIVAL MODELING OF EOC ACCORDING TO USE OF HRT AFTER DIAGNOSIS, TEMPORAL RELATION OF HRT USE
TO DIAGNOSIS AND HRT OVERALL DURATION OF USE AFTER DIAGNOSIS
HRT
No Cases
Deaths [n (%)]
HR (95% CI)1
HR (95% CI)2
499
150
13
8
9
120
30
293 (59)
51 (34)
5 (38)
6 (75)
4 (44)
36 (30)
15(50)
1.00 (reference)
0.46 (0.34–0.63)
0.59 (0.24–1.44)
1.16 (0.51–2.63)
0.55 (0.20–1.48)
0.41 (0.29–0.58)
0.64 (0.54 0.76)
1.00 (reference)
0.57 (0.42–0.78)
0.61 (0.25–1.47)
1.18 (0.51–2.70)
0.44 (0.16–1.19)
0.55 (0.38–0.79)
0.75 (0.62–0.89)
395
92
72
74
230 (58)
54 (59)
21 (29)
28 (38)
1.00 (reference)
1.02 (0.76–1.37)
0.39 (0.25–0.61)
0.55 (0.37–0.82)
1.00 (reference)
0.92 (0.68–1.25)
0.55 (0.35–0.87)
0.59 (0.39–0.87)
244
82
197
47
42
40
151 (62)
33 (40)
126 (64)
25 (53)
16 (38)
17 (42)
1.00 (reference)
0.52 (0.35–0.77)
1.00 (reference)
0.76 (0.50–1.18)
0.47 (0.28–0.79)
0.52 (0.31–0.88)
1.00 (reference)
0.65 (0.44–0.96)
1.00 (reference)
0.69 (0.45–1.08)
0.63 (0.37–1.07)
0.57 (0.34–0.96)
45
17
9
18 (40)
4 (23)
2 (22)
1.00 (reference)
0.44 (0.13–1.46)
0.48 (0.09–2.37)
1.0 (reference)
1.29 (0.28–6.14)
2.71 (0.35–20.91)
129
39
20
70 (54)
10 (26)
8 (40)
1.00 (reference)
0.40 (0.21–0.79)
0.73 (0.35–1.53)
1.0 (reference)
0.54 (0.28–1.06)
0.90 (0.43–1.92)
70
9
5
46 (66)
3 (33)
1 (20)
1.00 (reference)
0.36 (0.11–1.19)
0.25 (0.03–1.86)
1.0 (reference)
0.23 (0.06–0.91)
0.12 (0.02–1.04)
3
Any HRT use after diagnosis
Never
Ever
Duration use <1 year
Duration use 1–2 years
Duration use >2 years
Current users at time of data abstraction
Former users at date of data abstraction
Any HRT use in relation to diagnosis4
Never users before or after diagnosis
Users before diagnosis, never users after diagnosis
Never users before diagnosis, users after diagnosis
Users before and after diagnosis
Serous tumors
Never users after diagnosis
Ever users after diagnosis
Never users before or after diagnosis
Users before diagnosis, never users after diagnosis
Never users before diagnosis, users after diagnosis
Users before and after diagnosis
Mucinous tumors5
Never users after diagnosis
Ever users after diagnosis
Users before and after diagnosis
Endometrioid tumors5
Never users after diagnosis
Ever users after diagnosis
Users before and after diagnosis
Other tumors5
Never users after diagnosis
Ever users after diagnosis
Users before and after diagnosis
1
Hazard ratio estimates adjusted for age at diagnosis.–2Adjusted for age, FIGO stage and WHO grade. NB: additional adjustment for histological types in the analysis of all cancers combined did not entail meaningfully different results.–3Includes users and nonusers of any HRT before
diagnosis.–4Only for women without missing data for use of any HRT before and after diagnosis.–5There was no effect of duration of use for the
different histological subtypes.
diagnosis in this analysis, the confidence intervals (CIs) of the HR
included unity (HR 0.74, 95% CI 0.52–1.08). The analysis of histological subtypes––including a detailed analysis of serous
tumors––according to duration of use of HRT before diagnosis
(never, <3 years, 3 or more years of HRT use) and recency of
useanalyzed separately or in combination––did not reveal any
clear patterns of association We also added an indicator variable
for histological type in the models for all ovarian cancer together
in relation to all types of HRT grouped, and the results were basically unchanged (Table II).
Use of HRT after diagnosis and EOC
Women who were prescribed HRT after tumor diagnosis (44%)
were all below 60 years of age. Users of HRT after an EOC diagnosis were at a significantly lower risk of dying compared to never
users after diagnosis (multivariate HR 5 0.57, 95% CI 5 0.42–
0.78 when adjusting for age at diagnosis, tumor stage and grade of
differentiation; Table III). Results did not change substantially
when an indicator variable for the histological type was added in
the models of all invasive ovarian cancers considered together
(HR 5 0.61; 95% CI 5 0.45–0.84). The better survival was
observed for women with serous tumors (multivariate HR 5 0.65;
95% CI 5 0.44–0.96) and other tumors (HR 5 0.23, 95% CI 5
0.06–0.91) but not clearly for women with mucinous or endometrioid tumors (Table III).
The finding of a significantly better survival was observed both
amongst women who were current users and former users of HRT
at time of data abstraction from medical records (Table III).
Because of small numbers, this analysis was only possible when
considering all tumors together.
Combined use of HRT before or after diagnosis
We also compared never users of HRT both before and after diagnosis with:
a. Users before diagnosis, never users after diagnosis,
b. Never users before diagnosis, users after diagnosis and
c. Users before and after diagnosis.
The Kaplan–Meier 5-year survival curves for the combination
of use of HRT before and after EOC diagnosis are presented in
Figure 1.
Women who were users of HRT after diagnosis had a lower risk
of death, regardless of use of HRT before diagnosis (Table III).
We repeated these analyses for the different histological subtypes
of ovarian tumors. Women diagnosed with a serous tumor that had
used HRT both before and after diagnosis had a lower risk of
dying within 5 years of diagnosis. The use of HRT both before
and after diagnosis did not entail survival advantage for women
with mucinous, endometrioid and other ovarian tumors. However,
the number of patients in each subgroup was relatively small,
making estimates unstable in some subgroups (Table III).
The mean age of women who never used HRT (63.72 years; SD
7.02) was slightly higher than of users of HRT before diagnosis
only (61.58 years; SD 7.24), after diagnosis only (58.81 years, SD
7.75), and both before and after diagnosis (58.11; SD 6.26). There
was no difference in the proportion of women using chemotherapy
among these groups of women. Use of HRT before EOC diagnosis
was more common among white-collar workers (above 40%) than
among blue-collar workers (about 25%), but use of HRT after diagnosis did not differ substantially after diagnosis according to
social class (19% among blue-collar workers and 25% among
HRT AND OVARIAN CANCER SURVIVAL
2913
FIGURE 1 – Five-year EOC cause specific survival according to use of HRT before and after ovarian cancer diagnosis.
white-collar workers). However, the addition of indicator variables for socioeconomic status in the models already including age
(as a continuous variable) and multivariate models with FIGO
stage and WHO grade did not alter risk estimates for survival
according to HRT use after diagnosis at all.
Borderline ovarian tumors and use of HRT before
and after diagnosis
Among 150 women with BOT, 140 (93%) survived at least
5 years: 10 women died, 3 of them of ovarian cancer and 7 by
other causes. Information on use of HRT before diagnosis was
available for 141 women: 64 (45%) never used HRT before or after diagnosis; 29 (21%) used HRT before diagnosis, 72 (51%)
used HRT after diagnosis. There were 24 (17%) women who used
HRT both before and after diagnosis, 48 women (34%) used after
diagnosis only and 5 women (4%) used HRT before diagnosis
only. Of the 10 deaths for any cause occurring among women with
BOT, only 1 had used HRT before diagnosis. The 3 deaths due to
ovarian cancer among women diagnosed of BOT none had used
HRT before or after diagnosis. The overall mean survival time for
women with BOT was above 5 years.
Discussion
Invasive EOC
HRT before diagnosis. Overall, we found no clear differences
in EOC survival among women who used any type of HRT before
cancer diagnosis, and those who never used it. Similarly, use of estriol before cancer diagnosis was unrelated to EOC survival. There
was some indication of a better survival for users of HRT before
diagnosis of a serous EOC, although without a clear pattern
according to duration or recency of use. For endometrioid EOC––
for which results from a few studies have suggested a causal association with HRT27—we found no evidence of an association
between HRT use before diagnosis and survival. Similarly, no indication of better survival was observed for mucinous or other histological subtypes of EOC and HRT use before diagnosis.
Women who use HRT are likely to visit their doctors more regularly than women who do not use these drugs, either to get prescriptions or to undergo routine examinations. Thus, they may
have more opportunities to have malignancies––including ovarian
tumors––detected at early stages by routine examinations. This
was indeed what we observed in our study, where routine examination was the main mode of detection of tumors of high grade
and early stages. Therefore, we adjusted our analysis for FIGO tumor stage and WHO grade. However, HR estimates for HRT use
before cancer diagnosis remained virtually unaffected by these
adjustments.
Our results do not corroborate findings from the Cancer Prevention Study II,19,22 which suggested a worsened prognosis among
women using estrogens (without added progestins) for over 10
years. We found no such effect, regardless of duration or recency
of estrogen use before ovarian cancer diagnosis. However, the
number of women in our study that had used estrogens for more
than 3 years was rather small (28 cases/13 deaths), and we could
not perform analysis for longer durations of use of estrogens only.
It is plausible that longer duration of use could entail increased
mortality risk. In the US the most common type of estrogens used
before data collection of the Cancer Prevention Study II were conjugated equine estrogens, while in Sweden synthetic compounds
such are estradiol 17-B and estradiol valerate were predominant.
These compounds could, in theory, affect ovarian cancer survival
differently. Moreover, the Cancer Prevention Study II had a larger
number of ovarian cancer deaths (n 5 944) than our study (n 5
344), and had a very different study design: a large cohort answers
a questionnaire including information on estrogen use in the early
1980s, and vital status was accessed in 1996. In our study the
HRT information was collected a decade after, and most women
in Scandinavian reported using combined estrogen/progestin regimens, and use of estrogens without progestins was rare. In the
American study the history of hormone use was assessed at cohort
enrolment, and therefore information on estrogen use in very
recent years immediately preceding ovarian diagnosis were not
reported. Our study population in Sweden were ovarian cancer
cases identified in a nation-wide, population based case–control
study, where information on lifelong use of different types of
HRT was collected shortly after diagnosis, complemented by
abstraction of medical records for use of HRT after diagnosis.
Thus, the data retrieval methods were quite different between the
2 studies, making then differently predisposed to bias. Our find-
2914
MASCARENHAS ET AL.
ings of no association between use of specific hormonal preparations before ovarian cancer diagnosis––i.e., combined estrogen–
progestin hormone replacement, use of estriol or progestins
only––and survival are novel.
HRT after diagnosis. Among gynaecologic oncologists in
Sweden and elsewhere, estrogens without progestins have been
the most common type of hormone therapy prescribed among
women diagnosed with ovarian cancer.28 We found an indication
of better survival among women who used HRT after diagnosis,
particularly among patients with serous and other histological
types, and a suggestion of better survival among endometrioid
tumors too. We took into account that younger women were more
likely to be prescribed HRT after diagnosis (mean age below 60
years for users, and above 60 years for nonusers), and conducted
age adjusted multivariate analysis using 1 year age categories,
besides including stage and grade in the models. We cannot, however, exclude that these findings may reflect a subtle selection process that could not be accounted for in our analysis. Patients with
the best overall health status and prognosis as perceived by the
treating physician, for example those with a radical and complete
surgery including hysterectomy and bilateral salpingo-ophorectomy with omentectomy, were more likely to be prescribed HRT,
although there was no difference in HRT prescription after diagnosis according to chemotherapy use. However, the adjustment for
age at diagnosis, FIGO stage and WHO grade of the tumors,
which are the most important known indicators of survival, did
not affect HR estimates meaningfully. Use of HRT after diagnosis
was rather similar in blue-collar and white-collar workers, and the
inclusion of an even more detailed socioeconomic variable in the
statistical models had no impact on the risk estimates. This indicates that socioeconomic status is note explaining the better survival among users of HRT after diagnosis.
The biological mechanisms through which HRT used after
ovarian cancer diagnosis may act to influence tumor growth, and
ultimately survival remains unclear.
Our findings on use of HRT after ovarian cancer diagnosis contradict a few previously published studies. In the observational
study by Eeles et al.18 investigating HRT use after ovarian cancer
surgery in London, no statistically significant difference in disease
free survival was found between HRT users (about half having
used estrogens only and half estrogens combined with progestin)
and nonusers. Our study differs from Eeles’ on the age of the
patients: below 50 years in Eeles et al., and between 50 and 74
years in our study. Moreover, the way the data was analyzed by
Eeles et al. excluded deaths occurring in the first year of followup (the most severe cases which probably would not have had the
chance to receive HRT after diagnosis), as we included those in
our analysis.
In a observational study in Slovenia, Ursic Vrscaj et al.23
selected 24 patients with a diagnosis of ovarian serous cystadenocarcinoma who were treated with HRT (16 receiving estrognes
only and 8 receiving combined estrogens and progestins) after primary surgical treatment. Each such patient was compared with 2
control patients that did not receive HRT. The estimated risk of
death between the 2 patient groups was not statistically different
from each other. Limitations of our study include its design (a
‘‘randomization’’ backwards), and the very small number of
patients.
Guidozzi and Daponte20 randomized 130 patients younger than
59 years with invasive epithelial ovarian carcinoma to continuous
oral conjugated equine estrogen or no supplementation, and followed up the patients for a minimum of 48 months. The differences in overall survival between the 2 groups were not statistically
significant, although there was some indication of better survival
in the estrogen users group.
were alive after 5 years follow-up, and there was no indication that
use of HRT––before or after diagnosis––was associated with the
few occurring deaths among women with BOT. We have been
unable to identify other published studies with which to compare
these findings.
In addition to its large size, our study has a number of strengths
including a nationwide, population-based prospective design, reliable and detailed ascertainment of HRT use before diagnosis,
complete follow-up of cases and successful retrieval of medical
records with details on tumor characteristics and cancer treatment,
including prescription of HRT after cancer diagnosis. Furthermore, to our knowledge, it is the only study to address both, preand postdiagnostic exposures to HRT in relation to ovarian cancer
survival in the same study population. As a result, we were able to
adjust for known and hypothesized prognostic factors such as
stage and grade of the tumor, and mode of diagnosis.
One limitation of the present study was the possibility of selection bias in the parent study. The main reason for nonparticipation
in the parent study was patient’s refusal (24%), and it is conceivable that patients with advanced stages of disease may have been
less willing to participate.11 However, all the comparisons in our
study were made between women who accepted to participate,
and therefore can be considered as internally valid.
Of the women who accepted to participate in the parent study,
only 8 declined participation in the follow-up study, and only 1
was excluded due to physician’s denial to access the patient’s
records. We consider unlikely that these exclusions would affect
meaningfully our results.
Our patients were younger than the national average age of
ovarian cancer patients. The stage distribution was shifted towards
earlier stages compared to national estimates where stages III and
IV are slightly more prevalent and stage I and II less prevalent
than in our cohort.29 Also, we lack detailed information on nonparticipants, thus we do not know if they differed in HRT exposures or survival compared with study participants. Cause of death
in some instances could have been incorrectly recorded as due to
the cancer despite other severe comorbidity. Finally, we did not
have information on type of HRT use after diagnosis, although the
clinical practice in Sweden is to prescribe estrogens without progestin, particularly to women who undergo hysterectomy. We consider the abstracted information from medical records that was
done after ovarian cancer diagnosis as reliable, since it was
checked not only by the medical personnel in the treating hospitals, but also by our oncological nurse, and double checked by the
study gynaecological oncologist. All drugs prescribed to cancer
patients are systematically and carefully noted in the medical
records. Also, the reliability of our ascertainment of HRT use
before cancer diagnosis is evidenced by the clear associations we
found in studies about use of different types of HRT and cancers
of the breast,5 endometrial,9 and ovarian cancer,11 as well as hip
fractures.30 All these studies were carried out in Sweden using the
same self-administered questionnaire for data collection, and the
same group of women as controls. The associations reported in
these studies are now largely accepted and well established.
Given that ovarian cancer mortality rates overall are decreasing
while incidence rates seem to be stable in recent years,31 more
women are surviving for many years after a diagnosis of ovarian
cancer. Thus, assessing the risk-benefit and safety of use of HRT
after ovarian tumor diagnosis is of relevance from the patients’
perspectives. Our findings indicate that use of HRT before ovarian
tumor diagnosis does not affect survival, while HRT use after diagnosis may be associated with better survival for EOC patients.
Large randomized clinical trials on use of HRT after EOC diagnosis would be needed to confirm this possible association.
Borderline ovarian tumors
Because of small numbers we were only able to perform a basic
descriptive analysis of BOT. Almost all (94%) women with BOT
Acknowledgements
We are in indebted to all the gynecologists, pathologists and
oncologists who helped retrieving information.
HRT AND OVARIAN CANCER SURVIVAL
2915
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